RAC1 activation drives pathologic interactions between the epidermis and immune cells
Mårten C.G. Winge, … , Elizabeth A. Waterman, M. Peter Marinkovich
Mårten C.G. Winge, … , Elizabeth A. Waterman, M. Peter Marinkovich
Published June 13, 2016
Citation Information: J Clin Invest. 2016;126(7):2661-2677. https://doi.org/10.1172/JCI85738.
View: Text | PDF
Research Article Dermatology

RAC1 activation drives pathologic interactions between the epidermis and immune cells

Abstract

Interactions between the epidermis and the immune system govern epidermal tissue homeostasis. These epidermis-immune interactions are altered in the inflammatory disease psoriasis; however, the pathways that underlie this aberrant immune response are not well understood. Here, we determined that Ras-related C3 botulinum toxin substrate 1 (RAC1) is a key mediator of epidermal dysfunction. RAC1 activation was consistently elevated in psoriatic epidermis and primary psoriatic human keratinocytes (PHKCs) exposed to psoriasis-related stimuli, but not in skin from patients with basal or squamous cell carcinoma. Expression of a constitutively active form of RAC1 (RACV12) in mice resulted in the development of lesions similar to those of human psoriasis that required the presence of an intact immune system. RAC1V12-expressing mice and human psoriatic skin showed similar RAC1-dependent signaling as well as transcriptional overlap of differentially expressed epidermal and immune pathways. Coculture of PHKCs with immunocytes resulted in the upregulation of RAC1-dependent proinflammatory cytokines, an effect that was reproduced by overexpressing RAC1 in normal human keratinocytes. In keratinocytes, modulating RAC1 activity altered differentiation, proliferation, and inflammatory pathways, including STAT3, NFκB, and zinc finger protein 750 (ZNF750). Finally, RAC1 inhibition in xenografts composed of human PHKCs and immunocytes abolished psoriasiform hyperplasia and inflammation in vivo. These studies implicate RAC1 as a potential therapeutic target for psoriasis and as a key orchestrator of pathologic epidermis-immune interactions.

Authors

Mårten C.G. Winge, Bungo Ohyama, Clara N. Dey, Lisa M. Boxer, Wei Li, Nazanin Ehsani-Chimeh, Allison K. Truong, Diane Wu, April W. Armstrong, Teruhiko Makino, Matthew Davidson, Daniela Starcevic, Andreas Kislat, Ngon T. Nguyen, Takashi Hashimoto, Bernard Homey, Paul A. Khavari, Maria Bradley, Elizabeth A. Waterman, M. Peter Marinkovich

×

Figure 8

RAC1-dependent signaling in psoriatic keratinocytes of STAT3-, NFκB-, and IFN-related pathways.

Options: View larger image (or click on image) Download as PowerPoint
RAC1-dependent signaling in psoriatic keratinocytes of STAT3-, NFκB-, an...
Expression of (A) CARD14, (B) IFIH1, and (C) p-STAT3 (with and without IL-17A/F stimulation for 24 hours), as assessed by IDIF, in LacZ PHKCs, RAC1N17 PHKCs, LacZ NHKCs, and RAC1V12 NHKCs. CARD14, IFIH1, p-STAT3, red; RAC1 GTP, green; DNA, blue. (D) Western blot and (E) quantification of p-STAT3 after 0 and 24 hours of IL-17A/F stimulation. (F and H) Western blots and (G and I) quantification of p-STAT3 after 0, 10, and 90 minutes of stimulation with EGF or TNF-α. Scale bars: 25 μm (A–C), 10 μm A–C, insert Z-stack). Error bars represent SEM. (E) *P ≤ 0.05, by unpaired t test. Panels A–C are representative images from 3 replicate experiments. (D and E) n = 3 per condition; (F–I) n = 2 per condition.